The Genes Induced by Signal Transducer and Activators of Transcription (STAT)3 and STAT5 in Mammary Epithelial Cells Define the Roles of these STATs in Mammary Development

Abstract

Prolactin and leukemia inhibitory factor (LIF) have different roles in the adult mammary gland, which are mediated in part by the signal transducers and activators of transcription (STAT)5 and STAT3. In vivo studies have shown that STAT5 contributes to prolactin-dependent lobuloalveolar development and lactation whereas STAT3 mediates LIF-dependent epithelial apoptosis during postlactational involution. To understand the molecular basis of these STAT-dependent pathways, we demonstrate the ligand-independent effects of STAT5 and STAT3 in mammary epithelial cells in vitro and also identify the genes regulated by these related transcription factors. Thus, using conditionally active STAT3- or STAT5a-GyraseB fusion proteins, we observed that enforced and specific dimerization of STAT3 induced apoptosis whereas STAT5 induced differentiation of mammary epithelial cells. Furthermore, STAT5 attenuated apoptosis mediated by LIF, the physiological inducer of STAT3. Microarray analysis of STAT3- and STAT5-induced genes using this system demonstrated a marked specificity, which reflected their different physiological effects in vitro and in vivo. STAT5-specific gene targets included the milk protein genes alpha-casein and kallikrein-8 and the survival factors prosaposin and Grb10. STAT3-specific genes included the apoptosis regulators CCAAT enhancer binding protein-delta, phosphatidylinositol 3-kinase-regulatory subunits, purine nucleoside phosphorylase, and c-fos. These data illustrate that specific activation of STAT3 and STAT5 alone is sufficient to induce and suppress apoptosis, respectively, and that these transcription factors elicit their actions by inducing distinct subsets of target genes in mammary epithelial cells.

Bcl3 Selectively Promotes Metastasis of ERBB2-Driven Mammary Tumors

“…We have previously reported that expression of the NF-kB cofactor Bcl3 is dependent on Stat3 in mammary epithelial cells (5). This was confirmed for both Bcl3 mRNA and protein levels in normal mammary tissues ( Fig.…”

“…4). Previously, we had identified a panel of genes from murine mammary epithelial cells that were responsive to Stat3 (5). One of these Stat3-responsive genes, Bcl3, is a proto-oncogene originally described in B-cell lymphomas that has previously been shown to be constitutively expressed in a small study of breast cancer tissues (6,7).…”

“…Similarly, there is no known role for Bcl3 in either the normal or neoplastic mammary gland, yet is a cofactor of the inflammatory mediator NF-kB (6), which is associated with mammary epithelial cell survival (13) and malignant progression in HER2-and EGFR1-positive mammary tumors (14)(15)(16). We have previously proposed that Bcl3 may act as a link between Stat3 and NF-kB signaling in vivo (5,17).…”

Nucling, a Novel Apoptosis-associated Protein, Controls Mammary Gland Involution by Regulating NF-κB and STAT3

“…Our study also revealed that the activation of STAT3 was inhibited during mammary gland involution in the absence of Nucling, resulting in suppressed expression of C/EBP␦ mRNA, which is induced by STAT3 signaling (36). C/EBP␦ is known to be important in the apoptotic response in mammary glands as well as in diminished involution in C/EBP␦-deficient mice (37).…”

Butein is a novel anti-adipogenic compound

“…3T3-L1 cells were treated with butein for 12 and 24 h, and the expression of several known STAT3-regulated genes was analyzed. STAT3 is known to regulate several target genes, including KLF5 , P53 , CycD1 , C/EBP ␦ , and STAT3 ( 30 ). The known STAT3-downregulated genes KLF5 and P53 were induced by butein.…”